Zinc has been widely used as an anti-inflammatory and anti-arthritic agent for more than 3000 years. It has shown promising analgesic effect in a number of model systems. Previous studies found that zinc activated the pain-initiating TRPA1 channels and induced acute nocifensive behaviors. Therefore, zinc must execute its anti-nociceptive effect via alternative mechanisms. Our pilot studies show that pre-treatment of zinc desensitized TRPA1, suggesting that zinc can inhibit TRPA1 by inducing receptor desensitization like capsaicin to TRPV1. We also show that zinc suppressed TRPV1 function both in vitro and in vivo and genetic ablation of TRPA1 significantly reduced zinc inhibition of th TRPV1 function. The proposed experiments will test the hypothesis that extracellular zinc suppresses TRPA1/V1-mediated thermal and mechanical pain in both acute and chronic inflammatory models. We will investigate molecular determinants of zinc inhibition of TRPV1. We will also examine if TRPA1 activation is an upstream event of TRPV1 inhibition and test whether this regulatory mechanism is important for limiting zinc action in vivo using trpa1-/- mice and a specific TRPA1 blocker, HC-030031. The data resulting from these experiments will establish zinc as a novel anti-nociceptive agent by inhibiting two major pain-initiating TRP channels at the primary nociceptors and will reveal the molecular mechanisms by which zinc suppresses TRPV1 function. Our results will shed light on novel therapeutic strategies to target TRP channels for treatment of pain in the peripheral nociceptors without promoting on-target side effects in human patients.